Although complement plays an essential role in host defense, activated complement is a double-edged sword that has the potential to inflict substantial damage to self-tissues. One type of pathological conditions under which such complement-mediated damage has been widely assumed to occur is autoimmune disease. Recent works using complement- and Fc receptor-deficient mice, however, have challenged this widely held belief and cast doubt on the relevance of complement in autoimmune disease pathogenesis. As mammalian cells are usually well protected by membrane-bound complement regulatory proteins, we hypothesize that complement regulatory proteins represent important variables in determining the degree of complement involvement in the pathogenesis of autoimmune diseases. In this study, we will test this hypothesis in two well-established autoimmune disease models by using mice that are deficient in one or two central membrane complement regulatory proteins, namely decay-accelerating factor (DAF) and Crry. DAF/Crry and DAF/Fc receptor (FcR) double knockout mice will be generated by cross breeding DAF knockout mice with Crry knockout or FcR knockout mice, respectively. These mice, as well as the relevant single knockout and wild-type mice, will be used in the immune hemolytic anemia and anti-GBM-glomerulonephritis disease models to dissect the relative roles of complement, the FcR pathway, and membrane complement regulators in autoimmune disease pathogenesis. The specific aims are: 1) to generate DAF/Crry, and DAF/FcR double-deficient mice by cross breeding; 2) To determine if autoimmune hemolytic anemia is exacerbated in mice which lack DAF or DAF/Crry; 3) To determine if anti-GBM-glomerulonephritis is exacerbated in mice which lack DAF or DAF/Crry. These studies will test the in vivo function of membrane complement regulators and will help resolve the ongoing controversy regarding the role of complement in autoimmune disease pathogenesis. A better understanding of these issues will have direct therapeutic implications for human autoimmune diseases.